Combinatorial synthesis of peptide as well as small-molecule libraries has proven very useful as a method for generating vast numbers of highly diverse compounds (see for example Comprehensive Survey of Combinatorial Library Synthesis: 2002 Roland E. Dolle J. Comb. Chem., 2003, pp. 693-753). To fully exploit this high capacity of combinatorial chemistry to produce huge numbers of compounds several technologies have been developed that allow screening directly on the solid support (M. Meldal, 1994, METHODS: A companion to methods of enzymology 6:417-424). In the field of drug discovery such methods have successfully been applied for example for the identification of enzyme modulators. The library can be synthesized on resin beads that each carry one specific compound, and these “one-bead-one compound” libraries are then screened against the purified biological component of interest (e.g. cellular proteins or peptides),
Before progressing active compounds, identified though such procedure, further in the drug discovery process, the compound will have to be re-synthesized and tested for efficacy in a cell-based or in-vivo test system.
Novel ways to screen combinatorial libraries in a physiological more correct way are assumed to greatly accelerate the drug discovery process, and show importance in areas like chemo-genomics and chemo-proteomics.
Screening of combinatorial libraries in intact cells have been done by capturing mammalian or yeast cells together with a limited number of resin-beads in a “nanodroplet” (Borchart et al. Chem Biol 1997 4:961). Compounds immobilized on the resin are released through disruption of a photo-cleavable linker and the compound-associated effects on the intact cells are monitored.
In an alternative method the compounds are released through acidolysis resin-beads carrying the library members area are spread out on a lawn of mammalian cells, and the spatial localization of a cellular response is monitored and beads in that region is isolated, and the remaining compound is structure elucidated Jayawickreme et al, 1998,
Combinatorial peptide Library Protocols, Ed. Shmuel Cabilly, Humana Press, p. 107-128). WO03/038431 describes methods for screening combinatorial bead libraries by capturing cells from body fluids. Beads comprising a compound enabling cells to adhere to said bead may be selected.
US2003/0059764 describes multiplexed cell analysis systems using non-positional or positional arrays of coded carriers.